Inflammation is a cytokine-driven response by the innate immune system to destroy for example pathogens and damaged cells. In some disease conditions, such as rheumatoid arthritis (RA) and Crohn's disease, the regulation of the inflammatory system is impaired leading to tissue damages. Among the most studied inducers of inflammation are the cytokines interleukin-6 (IL-6) and tumor necrosis factor (TNF). IL-6 is also known as B cell Stimulatory Factor 2 (BSF2), Hepatocyte Stimulating Factor (HSF), Hybridoma Growth Factor (HGF) and interferon-beta 2 (IFNB2).
Human IL-6 consists of a single polypeptide chain of 184 amino acids with a molecular weight of 21 kDa, however a variable glycosylation pattern accounts for sizes varying between 21-26 kDa. IL-6 is secreted by a wide variety of cell types including T cells, B cells, monocytes, fibroblasts, hepatocytes, endothelial cells and keratinocytes. Downstream signaling induces the transition from acute inflammation to either acquired immunity or chronic inflammatory disease. IL-6 signaling and its regulation is complex and involves a number of factors and mechanisms. IL-6 signaling may occur via the classical IL-6 singling pathway, also known as the cis-signaling pathway, or via the trans-signaling pathway. In the classical IL-6 signaling pathway, circulating IL-6 binds to a membrane bound IL-6 receptor a (IL-6Rα) followed by recruitment of the membrane anchored gp130 co-receptor, which results in the formation of a ternary complex. This complex subsequently dimerizes with a second adjacent ternary complex leading to signal transduction via the gp130 moities (Boulanger et al., 2003, Science 300(5628): 2101-2104). In circulation, IL-6 can also exist as bound to soluble ectodomains of IL-6Rα. Such complexes are responsible for the trans-signaling mechanism, involving IL-6 dependent activation of any cells that express the co-receptor gp130 but lack IL-6Rα (Chalaris et al., 2011, Eur J Cell Biol 90(6-7): 484-494; Assier et al., 2010, Joint Bone Spine 77(6):532-6). The trans-signaling, or pro-inflammatory, pathway has been suggested to be the pathway most related to disease conditions, and thus the most preferable to block. In contrast, the classical signaling pathway is regarded as being responsible for important anti-inflammatory and regenerative processes (Scheller et al., 2011, Biochim Biophys Acta 1813(5): 878-888).
The anti-IL-6Rα antibody tocilizumab (Actemra®), has been approved for clinical use for IL-6 related disorders. Other drug candidates are also being developed in order to address different IL-6 triggered pathways. These include the antibodies CNTO136 (sirukumab) (Xu et al., 2011, Br J Clin Pharmacol 72(2): 270-281; Zhuang et al., 2013, Int J Clin Pharmacol Ther 51(3): 187-199) and MED15117 (Finch et al., 2011, J Mol Biol 411(4): 791-807), which bind to the IL-6 cytokine itself. Additionally the gp130-Fc fusion CR5/18, aimed at selectively blocking the trans-signaling pathway, is under development (Kopf et al., 2010, Nat Rev Drug Discov 9(9): 703-718; Chalaris et al., 2012, Dig Dis 30(5): 492-499).
The unpredictable and chronic nature of inflammatory diseases, as well as a high unmet medical need, warrants the development of new modes of treatment. Since tissue penetration rate is negatively associated with the size of the molecule, a relatively large antibody molecule inherently has poor tissue distribution and penetration capacity.
Thus, the use of monoclonal antibodies is not always optimal for therapy and there is continued need for provision of agents with a high affinity for IL-6. Of great interest is also the provision of uses of such molecules in the treatment, diagnosis and prognosis of IL-6 related disorders.